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The pancreas the gland responsible.

Insulin production and secretion.

Insulin receptors.

Glucose transporters.

Insulin action.

Abnormal carbohydrate metabolism.

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Insulin receptor

The first step in insulin action is the activation of tyrosine kinase of the sub-unit.

Initiate a series of events involving a cascade of phosphorylation-dephosphorylation.

Stimulation of intracellular glucose metabolism.

Initial step is the activation of the glucose transport system.

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Glucose uptake

GLUT-4 transporter

on cell membraneInsulin

insulin stimulated translocation ofglucose transporters

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Organ Glucose transporter HK coupler Classification

Brain GLUT1 HK-I Glucose dependent

Erythrocyte GLUT1 HK-I Glucose dependent

Adipocyte GLUT4 HK-II Insulin dependentMuscle GLUT4 HK-II Insulin dependent

Liver GLUT2 HK-IVL Glucose sensor

GK - cell GLUT2 HK-IVB ( glucokinase )Glucose sensor

Gut GLUT3-symporter ---- Sodium dependent

Kidney GLUT3-symporter ---- Sodium dependent

Glucose transporters

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B cell

High blood

glucose

Insulin

Impaired insulin releaseGlucose

uptake

FFA

FFA

Glucose Metabolism

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Skeletal

muscle

Brain

Splanchnic

bed

Adipose

tis

sue

Control NIDDM

Gluc

oseuptake(mg/

kg/min)

Insulin resistance is the major

contributor for the pathogenesis

of type 2 diabetes.

Resistance could be at the level

of insulin receptors or post

receptor defect.

Skeletal muscle is the major

contributor to insulin resistance

in patients with type 2 diabetes.

Hepatic glucose production

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Indogenous glucose

production should

balance with total body

glucose uptake.

Major production come

from glycogenolysis.

Major uptake is through

glucose oxidation.

0

0.5

1

1.5

2

2.5

Endogenous Glucose production Total Body Glucose Uptake

Glycogenolysis

Glycerol (2%)

Pyruvate (1%)

Lactate (16%)

Amino Acids (6%)

Other

Glycolysis

Glucose

Oxidation

Splanchnic

Glucose

Uptake

Hepatic glucose production

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Glucose

Fatty acid

Citrate

Acetyl CoA

Fatty acid

Glucose

Glucose 6-

Phosphate

Phospho-fructokinase

Frucose 6-

Phosphate

Frucose 1,6-

bisphosphate

Pyruvate

Acetyl CoA

Randle cycle

Glucose metabolism during fast state

Non-diabetic subject:

During an over night

fast liver will supplyenergy from glycogenstore.

Muscle will utilizeenergy from free fatty

acids (FFA) by Randlecycle.

This will decreaseglucose transportthrough cellularmembrane.

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Fasted state

Fructose 6-Phosphate

Fructose 2,6-bisphosphate

Fructose 1,6-bishosphate

Phosphoenolpyruvate

Oxaloacetate

pyruvate

Fed state

Fructose 6-Phosphate

Fructose 2,6-bisphosphate

Fructose 1,6-bishosphate

Phosphoenolpyruvate

Oxaloacetate

pyruvate

Glucose metabolism during fast and fed state

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Insulin deficiency

Blood glucose

Insulin resistance

Diabetes Mellitus is a group of metabolic disease characterized

by hyperglycemia resulting from defects in insulin secretion,

insulin action, or both.

The chronic hyperglycemia of diabetes is associated with

log-term damage, dysfunction, and failure of various organs,especially the eyes, Kidneys, nerves, heart, and blood vessels.

Pathogenesis of type 2 Diabetes Mellitus

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Natural History of Type 2 Diabetes Mellitus

Age 0-5+ 15-40+ 15-60+ 25-70+

Microvascular Complication

IGT Postprandial Fasting

Hyperglycemia Hyperglycemia

Macrovascular Complication

Disability

Insulin resistance

Hyperinsulinemia

HDL cholesterol

Triglyceride

Hypertension

Atherosclerosis

Normo-insulinemia

Retinopathy

Nephropathy

Neuropathy

Hypoinsulinemia

Blindness

Renal Failure

Amputation

IHDStroke

Genetic background for:

Insulin secretion

Insulin sensitivity

complications

Environmental factors:

Nutrition

Obesity

Physical inactivity

Disability

Death

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Natural History of Type 2 Diabetes Mellitus

Decrease Glucose-induced insulin

secretion

Insulin deficiency

Insulin resistance

Decrease Tissue response to insulin

Genetic

Acquired

GlucotoxicityLipotoxicity

Genetic

Acquired

Obesity

Vo2max

AgeSmoking

Increase Hepaticglucose production

Increase Cellular

glucose uptake

Hyperglycemia

Impaired beta

cell function

Post- receptor

defectDecrease Glucose transport

Decrease Insulin binding

BasalHyperinsulinemia

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